Total Serum Bilirubin Predicts Fat-Soluble Vitamin Deficiency

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J Pediatr Gastroenterol Nutr. 2014 December ; 59(6): 702707. doi:10.1097/MPG.0000000000000547.
Total Serum Bilirubin Predicts Fat-Soluble Vitamin Deficiency

Better Than Serum Bile Acids in Infants with Biliary Atresia
Veena L. Venkat, MD1, Benjamin L. Shneider, MD1, John C. Magee, MD2, Yumirle Turmelle,
MD3, Ronen Arnon, MD4, Jorge A. Bezerra, MD5, Paula M. Hertel, MD6, Saul J Karpen, MD,
PhD7, Nanda Kerkar, MD8, Kathleen M. Loomes, MD9, Jean Molleston, MD10, Karen F.
Murray, MD11, Vicky L. Ng, MD12, Trivellore Raghunathan, PhD13, Philip Rosenthal, MD14,
Kathleen Schwartz, MD15, Averell H. Sherker, MD16, Ronald J. Sokol, MD17, Jeffrey
Teckman, MD18, Kasper Wang, MD19, Peter F. Whitington, MD20, James E. Heubi, MD5, and
for the Childhood Liver Disease Research and Education Network (ChiLDREN)
1Department
of Pediatrics, Childrens Hospital of Pittsburgh of UPMC, Pittsburgh, PA

of Surgery and Department of Biostatistics, University of Michigan, Ann Arbor, MI
3Department of Pediatrics, Washington University, St. Louis, MO 4Department of Pediatrics,
Mount Sinai Medical Center, Cincinnati, OH 5Department of Pediatrics, Cincinnati Childrens
Hospital Medical Center, Cincinnati, OH 6Department of Pediatrics, Texas Childrens Hospital,
Atlanta, GA 7Department of Pediatrics, Childrens Health Care of Atlanta, Atlanta, GA
8Department of Gastroenterology, Childrens Hospital Los Angeles, Los Angeles, CA
9Department of Pediatrics, Childrens Hospital of Philadelphia, Philadelphia, PA 10Department of
Pediatrics, Riley Childrens Hospital, Indianapolis, IN 11Department of Pediatrics, Seattle
Childrens Hospital, Seattle, WA 12Department of Pediatrics, The Hospital for Sick Children,
Toronto, Ontario, Canada 13School of Public Health, University of Michigan, Ann Arbor, MI
14Department of Pediatrics, University of California San Francisco, San Francisco, California
15Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland 16National Institute of
Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
17Department of Pediatrics, University of Colorado School of Medicine and Childrens Hospital
Colorado, Aurora, CO 18Department of Pediatrics, Saint Louis University School of Medicine, Los
Angeles, CA 19Department of Pediatric Surgery, Childrens Hospital Los Angeles, Los Angeles,
CA 20Department of Pediatrics, Childrens Memorial Hospital, Chicago, IL
2Department
Abstract
ObjectiveFat soluble vitamin (FSV) deficiency is a well-recognized consequence of
cholestatic liver disease and reduced intestinal intraluminal bile acids. We hypothesized that serum
Corresponding Author: Veena L Venkat, MD, Division of Gastroenterology, Hepatology and Nutrition, Childrens Hospital of
Pittsburgh of UPMC, 4401 Penn Avenue, Pittsburgh, PA 15224, 412-692-7355 (fax), 412-692-5180 (phone), veena.venkat@chp.edu.
Trial Identification Number: NCT00294684, clinicaltrials.gov, childrennetwork.org
FINANCIAL DISCLOSURE: Dr Sokol is a consultant for and on the scientific advisory board of Yasoo Health, Inc, which is the
distributor for AquADEKs and ADEKs. The company had no involvement in designing the research, interpreting the data, or writing
the article; the other authors have indicated they have no financial relationships relevant to this article to disclose.
Venkat et al.
Page 2
bile acids (SBA) would predict biochemical FSV deficiency better than serum total bilirubin level
(TB) in infants with biliary atresia.
MethodsInfants enrolled in the Trial of Corticosteroid Therapy in Infants with Biliary Atresia
(START) after hepatoportoenterostomy were the subjects of this investigation. Infants received
standardized FSV supplementation and monitoring of TB, SBA and vitamin levels at 1, 3 and 6
months. A logistic regression model was used with the binary indicator variable insufficient/
sufficient as the outcome variable. Linear and non-parametric correlations were made between
specific vitamin measurement levels and either TB or SBA.
ResultsThe degree of correlation for any particular vitamin at a specific time point was higher
with TB than SBA (higher for TB in 31 circumstances versus 3 circumstances for SBA). Receiver
operating characteristic (ROC) shows that TB performed better than SBA (AUC 0.998 vs. 0.821).
Including both TB and SBA did not perform better than TB alone (AUC 0.998).
ConclusionWe found that TB was a better predictor of FSV deficiency than SBA in infants
with biliary atresia. The role of SBA as a surrogate marker of FSV deficiency in other cholestatic
liver diseases, such as PFIC, alpha-one antitrypsin deficiency and Alagille syndrome where the
pathophysiology is dominated by intrahepatic cholestasis, warrants further study.
Keywords
fat soluble vitamin; cholestasis; serum bile acid; biliary atresia; bilirubin
Introduction
Cholestatic liver disease results from diminished bile flow leading to decreased intestinal
intraluminal bile acids and increased levels of serum bile acids and serum total bilirubin.
One well recognized consequence of cholestatic liver disease and reduced intraluminal bile
acids is nutritional deficiency since bile acids are essential for fat and fat soluble vitamin
absorption. Intestinal bile acids must be present in excess of the critical micellar
concentration for optimal absorption of fat and fat soluble vitamins and commonly fall
below this level in cholestasis.
The consequences of fat soluble vitamin deficiency are well described. Recognition of
deficiency states and provision of adequate oral or parenteral supplementation with close
monitoring is critical to optimal management of infants and children with cholestatic liver
disease such as biliary atresia.
Biliary atresia is a progressive cholangiopathy that causes fibrotic obliteration of intra- and
extrahepatic bile ducts in infants and presents in the first two months of life. Recent analysis
of prospectively collected data from infants with biliary atresia in the Childhood Liver
Disease Research and Education Network (ChiLDREN) funded by the National Institutes of
Health, characterized rates of fat soluble vitamin deficiency in patients with biliary atresia.
Fat soluble vitamin deficiency was inversely correlated to serum total bilirubin and was
more prevalent in infants whose serum total bilirubin was greater than 2 mg/dl. 1
Venkat et al.
Page 3
Prior studies have proposed that serum bile acids may be a more precise marker of
cholestasis in chronic cholestatic liver disease.24 We therefore hypothesized that serum bile
acid (SBA) would predict biochemical fat soluble deficiency better than total bilirubin (TB)
level in infants with biliary atresia. The previously reported study has now been reassessed
relative to serum bile acids to test this hypothesis.
Materials and Method
Infants enrolled in the Trial of Corticosteroid Therapy in Infants with Biliary Atresia
(START) conducted by the NIH funded ChiLDREN study were the subjects of this
investigation. The study was a randomized double-blinded, placebo-controlled trial of
corticosteroid therapy after hepatoportoenterostomy.5 Fat soluble vitamin preparation
(ADEK, AquADEK), vitamin K and ursodiol were provided to the subjects of the study as
part of a cooperative agreement between the manufacturer and the NIDDK. Standardized
dosing after hepatoportoenterostomy was established for study participants.5 Target ranges
and dosing recommendations for further supplementation with individual fat soluble
vitamins was provided to the centers. (Table 1) Informed consent was obtained from the
parent or guardian for all study participants and IRB approval was obtained at each local
center.
Serum concentrations of fat soluble vitamins, RBP and total lipids were performed in the
Clinical Translational Research Center Core Laboratory at the Childrens Hospital (Aurora,
CO) as previously described.6 Pediatric reference ranges used for target vitamin levels in
this study followed published criteria.7,8 Vitamin insufficiency was defined as vitamin
measurements (serum level for 25 hydroxyvitamin D, retinol: retinol binding protein for
vitamin A and serum alpha tocopherol:total lipid ratio for vitamin E below the lower limit of
the normal range or elevated INR for vitamin K. (Table 1) Measures of vitamin sufficiency
included both vitamin E and vitamin E:lipid ratio to ensure compensation for hyperlipidemia
associated with cholestasis. Similarly, both retinol and retinol: RBP ratio was calculated as
indices of vitamin A status to assess hepatic stores.
Total SBA was determined by enzymatic and colorometric method (Diazyme Laboratories,
Poway, CA) in the Clinical Translational Research Center Core Laboratory at Cincinnati
Childrens Hospital Medical Center. Bile acids are converted to 3-oxo bile acids with 3hydroxysteroid dehydrogenase (3-HSD) with concomitant reduction of NAD+ to NADH.
Age-specific reference ranges were determined in this laboratory in 1995 1996. The ranges
are published in Pediatric Reference Ranges, 2nd Ed., AACC Press, Washington D.C., 1997.
Blood testing for prothrombin time/INR, TB, total SBA, total lipids, retinol binding protein
(RBP), retinol, alpha tocopherol and 25 hydroxyvitamin D was performed at 1, 3, and 6
months after HPE as part of the START protocol. Vitamin levels, PT/INR, TB and SBA
were available 1, 3, and 6 months post-HPE on varying numbers of subjects. A separate
analysis was performed for each time point. Treatment with steroids after HPE did not affect
outcome by multiple measures including bilirubin at any time point up until 24 months of
age, duration of bile drainage, or survival without liver transplantation. As such, subjects in
this study were considered in aggregate without knowledge of whether they had received
Venkat et al.
Page 4
placebo or steroids with respect to all measures.5 All patients received supplementation
according to the guidelines noted independent of their randomization status.
Initial analyses of a relationship between TB or SBA and vitamin levels were performed by
linear regression. Given the nonlinear relationship between the vitamin levels and TB and
SBA, Kendalls tau was also computed between the vitamin level and TB or SBA and
assessed for statistical significance.
To assess the value of using both TB and SBA as biomarkers to identify subjects with
vitamin insufficiency, a logistic regression model was used with the binary indicator
variable insufficient/sufficient as the outcome variable. Three regression models were
compared: TB alone as the predictor, SBA alone as the predictor and both TB and SBA as
predictors. The receiver operating characteristics (ROC) curve under each model was used
to evaluate TB or SBA as risk factors for insufficiency. Specifically, the area under the
curve (AUC) of the two ROC curves was assessed for statistical significance. A bootstrap
procedure was used to compute the standard error for the difference in the area under the
curve for ROCs for any two models. Using the ROC curves for the TB only model and the
SBA only model, the best TB and SBA cutoff values (those values that maximize the
probability of correctly classifying a subject as vitamin insufficient/sufficient) were
determined. All analyses were performed using SAS/STAT (SAS Institute Inc. 2008. SAS/
STATR 9.2 Users Guide. Cary NC: SAS Institute Inc.)
Results
Between September 21, 2005 and October 31, 2008, 92 infants with BA were enrolled in the
study. Data were collected up to July 1, 2009. Information was available at entry, 1, 3 and 6
months after HPE in 92, 86, 83 and 61 infants, respectively. Forty-seven percent of the
subjects were male, 23% Hispanic, 60% White, 16% Black, and 24% other races (Asian,
Native American and unknown).
Analysis was performed to determine whether SBA or TB levels were a better predictor of
vitamin deficiency at time points after HPE. Comparative scatterplots of serum 25hydroxyvitamin D plotted against SBA and TB levels with spline correlation is depicted in
Figure 1.
Linear (Pearsons) and non-parametric (Kendalls) correlations were made between specific
vitamin measurement levels and either serum TB or SBA concentrations at 1, 3 and 6
months after HPE (Tables 2 and 3, respectively). Negative correlations were demonstrated
between TB or SBA and vitamins A, D and E measurements, and positive correlations were
demonstrated with INR. The correlation for any particular vitamin at a specific time point
was higher with serum TB than SBA and equally distributed across linear (15
circumstances) and non-parametric (16 circumstances) correlations. In total, TB showed a
greater degree of correlation with specific vitamin levels at 31 time points compared to 3
circumstances for SBA.
An alternative analysis utilized the ROC of the ability of either TB or SBA to predict a
specific or any vitamin insufficiency. Receiver operating characteristic (ROC) in the
Venkat et al.
Page 5
predictive model for any FSV deficiency at 6 months shows that TB performed better than
SBA (AUC 0.998 vs. 0.821). Including both TB and SBA level did not perform better than
total bilirubin alone (AUC 0.998). (Figure 2) In a comparison between TB and SBA for
specific time points for each vitamin level, ROC AUC of TB was of greater magnitude
(p<0.05) for more time points. (Table 4)
Optimal cut-off values for predicting vitamin insufficiency were generally in the range of
3-8 mg/dL for TB and 100 to 200 mcMol/Lfor SBA.
Discussion
Contrary to our hypothesis when we initiated this study, we found that serum total bilirubin
was a better predictor of fat soluble vitamin deficiency than serum bile acids in infants with
biliary atresia when sequential fat soluble vitamin levels were assessed over the three year
timeframe of the study. Combining both total bilirubin and serum bile acids in the ROC
analysis did not improve the results compared to total bilirubin alone.
In cholestasis, fat soluble vitamin deficiency results from impaired bile flow leading to
inadequate concentrations of bile acids in the intestinal lumen. The absorption of fat soluble
vitamins requires formation of micelles that solubilize them into the aqueous environment of
the intestinal lumen and facilitates their passive diffusion across the enterocyte. Bile acid
levels in the intestinal lumen below a critical micellar concentration lead to impaired
absorption of fat and fat soluble vitamins in cholestatic liver disease.
The pathophysiology of biliary atresia relates to an inflammatory and progressive fibrotic
obstruction of the extrahepatic and intrahepatic biliary tract progressing at variable rates to
end stage liver disease. Since the predominant effect is extrahepatic obstruction, TB may
have an inordinately weighted contribution as a biochemical manifestation of cholestasis.
This occurs despite the well described physiologic role of bile acids as the principal driver of
bile flow.
This contrasts with other disorders such as Alagille Syndrome, alpha-1-AT deficiency or
PFIC 1, 2 or 3 in which intrahepatic cholestasis is the predominant pathophysiologic finding.
Because of the unique pathophysiology of these cholestatic conditions in infancy and
childhood, bilirubin might not be as robust a predictor of submicellar concentration of bile
acids in the intestinal lumen and SBA might prove more effective. SBA in these conditions
may be markedly elevated in the presence of normal or minimally elevated serum
bilirubin. 9,10 Even in the absence of overt jaundice, patients with these disorders can
present with clinical sequelae of fat soluble vitamin deficiency such as rickets, fractures and
bleeding diathesis. 10,11
The results of previous studies in patients with intrahepatic cholestasis (including primary
biliary cirrhosis, alpha-1-antityrpsin deficiency, Alagille Syndrome and presumed PFIC
patients) have suggested that the SBA concentration might be a surrogate for intraluminal
bile acid concentration and thereby could be used as a predictor of fat soluble vitamin
absorption.12 A serum cholyglycine between 34-118Mol/l was associated with intraluminal
bile acid concentration below 2 mMol /L (the proposed CMC) and likely associated with fat
Venkat et al.
Page 6
and fat soluble vitamin deficiency. Serum CG likely constitutes no more than 25-30% of the
total bile acid pool with concomitant contribution to the total serum bile acid concentrations.
It is therefore possible to extrapolate that a CG of 34-118 Mol/l might be equivalent to total
bile acid levels measured by the enzymatic method, used in the current study, of 136-472
Mol/l thereby approximating the levels of 100-200 Mol/L as the threshold associated with
vitamin malabsorption in this study.12
This relationship between SBA levels, intestinal concentrations of bile acids, and vitamin E
absorption has also been described in patients with primary biliary cirrhosis. Biochemical
markers of cholestasis including serum bilirubin and serum cholyglycine were significantly
higher in patients with vitamin E deficiency. More importantly, absorption of vitamin E, as
measured by analysis of serial levels after an oral loading dose, was impaired in patients
with more advanced liver disease based on histologic stage as well as in patients with
biochemical evidence of deficiency at baseline.13
The administration of a liquid multiple FSV preparation (ADEKs or AquADEKs made

with tocopherylpolyethylene glycol-1000 succinate (TPGS)) along with additional vitamin
K was part of the routine clinical care for this study cohort. Oral tolerance testing of TPGS
during the course of studying its use to treat vitamin E deficiency in children with chronic
cholestatic conditions has shown improved intestinal absorption with this water soluble
preparation compared to conventional formulations.13 The need to bypass physiologic
enteral absorption with a water soluble compound or intramuscular/intravenous preparations
to attain a state of sufficiency underscores the obligate role of bile acids in fat soluble
vitamin absoprtion in patients with cholestatic liver disease. These studies in vitamin E are
more accurate markers of absorption as vitamin D is synthesized endogenously and
prothrombin time and INR are relatively crude measures of vitamin K deficiency. 1416
Though the use of an available TPGS-based compound is likely to have attenuated the
degree of fat soluble vitamin deficiency1 biochemical evidence of FSV insufficiency is still
common in infants with biliary atresia at all time points (1, 3 and 6 months after HPE) for
vitamin A (29%36% of patients), vitamin D (21%37%), vitamin K (10%22%), and
vitamin E (16%18%). It is therefore not surprising that the correlation of TB are of
increasingly greater magnitude over time after HPE (1, 3, 6 months), as FSV insufficiency is
persistent despite treatment with ADEK and AquADEK particularly in patients with
cholestasis measured by a TB of >2 ng/dl.
Fat soluble vitamin insufficiency in infants and children with cholestatic liver disease is
detected by regular screening. Additionally, after FSV supplementation is prescribed,
ongoing monitoring of fat soluble vitamin levels is necessary to ensure sufficiency and to
evaluate for toxicity. Measurement of FSV levels in infants and children has practical
limitations including blood volume and cost. A reliable biomarker such as the TB above
which FSV deficiency is likely could provide a method of screening by which patients
should be aggressively monitored for fat soluble vitamin deficiency. Using a cutoff of 3-4
mg/dl TB as an indicator of risk for vitamin deficiency in infants with biliary atresia might
be cost effective and subject only the most at risk patients to additional phlebotomy and
Venkat et al.
Page 7
blood collection to monitoring and prevention of FSV insufficiency in patients with biliary
atresia.
Determinants of vitamin D status include not only cholestasis and malabsorption, but also
synthetic function of the liver, skin pigmentation and light exposure. Though concentrations
representing vitamin D sufficiency/insufficiency are generally accepted, there is no
published vitamin D screening guideline either for the general pediatric population or for
children at risk. These multiple factors contributing to vitamin D sufficiency may require
screening in infants and young children with biliary atresia even if the serum bilirubin is
low. Vitamin D supplementation in infants and young children with biliary atresia should
follow published recommendations for daily vitamin D intake. 17
There are a few limitations of this study. Though standardized vitamin supplementation and
dosing was encouraged as part of the study protocol, center-specific, routine clinical care
was permitted at the individual centers. The timing of collection of serum for bile acid
measurement was not standardized and there is a recognized postprandial rise in serum bile
acids in normal infants, children and adults.18 In cholestatic patients, the differences
between fasting and postprandial SBA is likely less significant and this likely had a minimal,
if any, effect, on the observed results.19 The ChiLDREN and START studies include 14
clinical sites, geographically located across the United States and should be generalizable to
all infants with biliary atresia. However, because this study was specific to infants with
biliary atresia, the findings may not be applicable to infants with other liver diseases in
which serum bile acids may be required to diagnose cholestasis or to determine if ongoing
treatment with ursodehoxycholic acid and fat soluble vitamin supplementation is needed.
The findings of the present study suggest that serum total bilirubin in infants with biliary
atresia is a robust biomarker of FSV insufficiency and it is superior to serum bile acid
measurement. This is a practical finding as measurement of TB is more readily available
than SBA. The role of serum bile acids as a surrogate marker of FSV deficiency in other
cholestatic liver diseases in children, with pathophysiologies different from biliary atresia,
warrants further study.
Acknowledgments
FUNDING: This work was supported by U01 grants from the National Institute of Diabetes, Digestive and Kidney
Disease (DK62453 [Dr. Sokol], DK84538 [Dr. Wang], DK62500 [dr. Rosenthal], DK62470 [Dr. Karpen],
DK62436 [Dr. Whitington], DK84536 [Dr. Molleston], DK62503 [Dr. Schwarz], DK62452 [Dr. Turmelle],
DK62445 [Dr. Arnon], DK62497 [Dr. Bezerra], DK62481 [Dr. Loomes], DK62466 [Dr. Shneider], DK84575 [Dr.
Murray], DK62470 [Dr. Hertel]) and CTSA grants from the National Center for Advancing Translational Sciences
(UL1TR000154 [Colorado], UL1TR000130 [Los Angeles], UL1TR000004 [San Francisco], UL1TR000454
[Atlanta], UL1TR000150 [Chicago], UL1TR000006 [Indianapolis], Ul1TR000424 [Baltimore], UL1TR000448
[St.Louis], UL1TR000077 [Cincinnati], UL1TR000003 [Philadelphia], UL1TR000005 [Pittsburgh], UL1TR000423
[Seattle]. Funded by the National Institutes of Health.
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Page 9

Figure 1.
Comparative scatterplots of 25-hydroxyvitamin D plotted against SBA and TB levels. Spline

correlation depicted by the solid line with a more apparent inverse relationship between total
bilirubin and 25-hydroxyvitamin D.
Venkat et al.
Page 10

Figure 2.
Comparison between TB and SBA for specific time points for each vitamin level. The ROC
AUC of TB had was of greater magnitude (p<0.05)
Venkat et al.
Page 11
Table 1
Target Fat Soluble Vitamin Levels and Replacement Regimens

Vitamin
Target range
Supplementation strategy
A(retinol)
19 77 g/dL
retinol:retinol
binding protein
molar ratio > 0.8
Increments of 5000 IU(up to 25 50,000 IU/day) orally

or monthly intramuscular administration of 50,000 IU
D
(25-hydroxy
vitamin D)
15 45 ng/ml
Increments of 1200 to 8000 IU orally daily of

cholecalciferol or ergocalciferol
Alternatively calcitriol at 0.05 to 0.20 g/kg/day
E
(alpha
tocopherol)
3.8 20.3 g/ml

Vitamin E:total
serum lipids
ratio > 0.6 mg/g
Increments of 25 IU/kg of TPGS orally daily(to 100

IU/kg/day)
K
(phytonadione)
INR1.2
1.2 < INR 1.5 2.5 mg vitamin K orally daily

1.5 < INR 1.8 2.0 5.0 mg vitamin K intramuscular
and 2.5 mg vitamin K orally daily
INR > 1.8 2.0 5.0 mg vitamin K intramuscular and 5.0
mg vitamin K orally daily

Venkat et al.
Page 12
Table 2
Linear Correlation Analysis of Vitamin Level Relative to Total Bilirubin (TB) or Serum Bile Acids (SBA)
TB correlation
(mg/dl)
SBA correlation
(Mol/L)
correlation
P-value
correlation
P-value
1 month
.300
.05
.372*
<.01
3 months
.576
<.01
.408
<.01
6 months
.625
<.01
.394
.02
1 month
.321
.05
.149
.35
3 months
.398
.03
.395
.01
6 months
.652
<.01
.278
.15
1 month
.496
<.01
.227
.12
3 months
.349
.03
.127
.40
6 months
.512
<.01
.231
.20
1 month
.588
<.01
.362
.03
3 months
.602
<.01
.457
<.01
6 months
.498
.02
.525
<.01
1 month
.458
<.01
.326
.03
3 months
.600
<.01
.360
.02
6 months
.714
<.01
.680
<.01
1 month
.495
<.01
.135
.39
3 months
.536
<.01
.318
.06
6 months
.595
<.01
.200
.30
Retinol (A)
(g/dl)
Retinol/RBP
(molar ratio)
Alpha tocopherol
(E) (g/ml)
E/lipids
(mg/g)
25hydroxyvitamin D
(ng/ml)
INR (K)
Correlation in bold has p-value < 0.05 and is of greater magnitude in a comparison between TB and SBA
Venkat et al.
Page 13
Table 3
Nonparametric Correlation Analysis of Vitamin Levels Relative to Total Serum Bilirubin (TB) or Serum Bile
Acids (SBA)
TB (mg/dl) correlation
SBA (Mol/L) correlation
correlation
P-value
Correlation
P-value
1 month
.236
.03
.251*
.01
3 months
.395
<.01
.285
<.01
6 months
.585
<.01
.395
<.01
1 month
.138
.23
.000
1.00
3 months
.352
<.01
.290
<.01
6 months
.493
<.01
.289
.03
1 month
.346
<.01
.168
.09
3 months
.329
<.01
.187
.07
6 months
.418
<.01
.143
.24
1 month
.507
<.01
.257
<.01
3 months
.506
<.01
.397
<.01
6 months
.496
<.01
.492
<.01
1 month
.333
<.01
.197
.06
3 months
.356
<.01
.227
.03
6 months
.689
<.01
.536
<.01
1 month
.308
<.01
.192
.08
3 months
.349
<.01
.303
<.01
6 months
.449
<.01
.055
.68
Retinol (A)
(g/dl)
Retinol /RBP
(molar ratio)
Alpha tocopherol (E)

(g/ml)
E/lipids
(mg/g)
25hydroxyvitamin D
(ng/ml)
INR (K)
Correlation in bold has p-value < 0.05 and is of greater magnitude in a comparison between TB and SBA

.870
.870
3 months
6 months
.765
.801
6.5
5.0
nc^
.964
6 months
13.2
12.8
.929
.849
3 months
6 months
.941
6 months
1 month
.872
.801
3 months
INR (K)
(>1.2)
.643
1 month
.856
1.2
.608
.602
10.5
.556
.750
3.5
5.0
.890
6 months
.804
.784
.750
.585
3.1
10.2
.904
3 months
25-hydroxyvitamin D
(<15 ng/ml)
6.1
.904
1 month
E/lipids
(<0.6 mg/g)
6.1
.801
1 month
.660
.814
1.4
.767
Alpha tocopherol (E)

(<3.8 g/ml)
.683
3.7
.665
3 months
.531
.903*
AUC
6.9
Cut off
117
172
90
184
261
215
164
261
101
268
73
142
233
125
169
234
Cut off
SBA ROC
(M)
1 month
Retinol/RBP
(Molar ratio < 0.8)
.694
1 month
Retinol
(<20 g/dl)
AUC
TB ROC
(mg/dl)
.11
<.01
.04
.29
.98
.06
.34
nc^
.17
.69
<.01
nc^
0.17
.01
.01
.01
P-value
(favored
predictor
bolded
ROC Analysis of Prediction of Vitamin Deficiency By Total Serum Bilirubin (TB) or Serum Bile Acids (SBA)
Table 4
Venkat et al.
Page 14
.856
.931
.987
1 month
3 months
6 months
.774
.776
.821
5.0
.792
3.5
7.5
.938
6 months
.805
AUC
3.1
3.5
.820
3 months
Any Deficiency
Cut off
114
168
104
114
169
Cut off
<.01
<.01
.18
.18
nc^
nc - not calculable
ROC AUC in bold has p-value < 0.05 and is of greater magnitude in a comparison between TB and SBA

AUC
P-value
(favored
predictor
bolded

SBA ROC
(M)
TB ROC
(mg/dl)
Venkat et al.
Page 15

Total Serum Bilirubin Predicts Fat-Soluble Vitamin Deficiency

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Total Serum Bilirubin Predicts Fat-Soluble Vitamin Deficiency

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